Chemical genomics for fast and integrated target identification and lead optimization

Chemical genomics methods can address biological questions that are not amenable to genetic manipulation or structural genomics approaches'. The idea of using small molecules in cell-based assays to discover biologically active compounds is one of the earliest concepts in medicinal chemistry and pharmacology. Now, the major focus of discovery efforts has turned to the identification of the druggable portion of the genome that is linked to pathological states and is able to interact with the drug-like chemical space, restoring normal functions.(2) In contemporary chemical genomics approaches, cell-based assays and affinity-based approaches work together to identify the function of genes that are still unknown. While forward chemical genomics starts with probing the genome using small molecule interaction at the cellular level (cell-based approach), reverse chemical genetics starts with an identified novel protein target and screens for small molecules that affect its activity and then tests whether the small molecule causes a phenotypic or gene-expression change associated with a disease. Thus, the first step is identifying small molecule interaction in a genome-wide or proteome-wide manner using activity/affinity-based approaches, while the second step is a target validation in whole-cell assays.